The objectives of the proposed research are to identify some of the mechanisms by which histocompatibility-linked (H-linked) immune response (Ir) genes control development of antibody and cell-mediated immunity to the synthetic antigen L-glutamic acid 60-L-alanine 30-L-tyrosine 10 (GAT) ant the natural protein antigens, insulin and proinsulin. The specific aims are to characterize the functional differences between antigen-specific T cells and B cells and M phi from responder and nonresponder mice. These studies have been designed to test the hypothesis that nonresponsiveness to a particular antigen reflects a defect in cell-cell communication and furthermore, that such a defect can occur at any position in the pathway of cell-cell interactions that involve products of I-subregion genes. The identification of the defects in genetic nonresponder mice should provide valuable insight into regulatory pathways that control the immune system. This information is necessary to characterize disease processes that result from an imbalance in the immunological apparatus and to devise rational therapeutic measures to correct these imbalances. Last, two of the antigens used in these studies, insulin and proinsulin, are biologically active proteins of clinical relevance. Since insulin-replacement therapy frequently results in complications caused by production of anti-insulin antibodies, analysis of immune responses may contribute to the development of methods to specifically prevent production of anti-insulin antibodies in insulin-dependent diabetic patients.